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PROTECT trial: Pegloticase for Uncontrolled Gout in Kidney Transplant Recipients

Presented by
Dr Bradley Marder, Horizon Therapeutics, in Deerfield, Illinois
ASN Kidney Week 2022
Phase 4, PROTECT
Early findings from the PROTECT trial, presented at the American Society of Nephrology’s Kidney Week, held in Orlando, FL from Nov 4-7, 2022, demonstrate substantial and sustained serum urate reduction in renal transplant recipients with uncontrolled gout. These findings are consistent with other reports on the effect of immunomodulation use with pegloticase.

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Automatisch gegenereerde beschrijving" /> Gout is a chronic disease of monosodium urate deposition characterized by arthritis flares and disability. Flares are inflammatory, often intensely painful, and debilitating, separated by asymptomatic intercritical periods. Advanced disease develops in approximately 15% of patients [1] and is characterized by subcutaneous nodules composed of monosodium urate (tophi), unremitting articular inflammation, and potential joint erosion and deformity.

Kidney transplant recipients have a high prevalence and severity of gout. Pegloticase (pegylated recombinant uricase) rapidly metabolizes urate and efficacy is not impacted by CKD stage. Immunomodulator co-therapy with pegloticase has improved treatment response rates over phase 3 monotherapy trials by attenuating anti-drug antibodies. This ongoing Phase 4 trial (PROTECT; NCT04087720) examined safety and efficacy of pegloticase in KT patients with uncontrolled gout (UCG). The data were presented by Abdul Abdellatif, MD, FASN, board-certified nephrologist at Baylor College of Medicine and at CLS Health, TX.


The primary endpoint was the number of patients reaching serum urate levels <6 mg/dL for ≥80% of time at month 6, with an additional 3 months of follow up. Secondary endpoints included the Health Assessment Questionnaire (HAQ) pain (most severe: 100) and Disability Index (HAQ-DI) scores.

In total, 20 patients were enrolled (mean±SD; 53.9±10.9 years of age, time since renal transplant: 14.7±6.9 years, serum urate: 9.4±1.5 mg/dL, gout duration: 8.4±11.6 years; all on ≥2 immunomodulation agents). At the time of analysis, 10 patients completed treatment, 3 discontinued study, 2 met serum urate monitoring rules (pre-dose SU>6 mg/dL at 2 consecutive visits) and discontinued pegloticase, and 5 were ongoing. All patients experienced initial substantial reductions in serum urate, which was maintained in the majority; 2 patients met monitoring rules. At week 24, no notable eGFR changes were observed. In patients who completed treatment, HAQ-pain and HAQ-DI scores improved by 26.7±30.3 (baseline: 35.9±30.2) and 0.2±0.5 (baseline: 1.0±1.0), respectively, at Week 24 (n=10). Safety analyses revealed 7 serious adverse events (2 cellulitis,1 duodenal ulcer, 1 sepsis, 1 atrial fibrillation, 1 diverticulitis, and 1 localized infection), none of which were deemed to be related to pegloticase, were reported in 5 patients. No anaphylaxis events occurred. The authors concluded that future studies need to look at long-term benefits of controlling gout. Several meta-analyses have shown that patients who develop gout after transplant have increased risk for transplant complications and rapid progression to end-stage renal disease, compared with those who do not develop gout. During the PROTECT trial, the investigators saw a reduction in systolic, diastolic, and mean arterial blood pressure during treatment, which was sustained in the follow-up period. It did not have any negative effect on the kidney function during the clinical trial compared to baseline. There is additional research needed.

Medicom spoke with co-author of this study, Dr Bradley Marder, from Horizon Therapeutics, in Deerfield, Illinois.
Medicom: What is the unmet need in gout patients currently?

“The biggest unmet that requires addressing for treating uncontrolled gout is the fact that once a patient has gout for long enough to accumulate a sizeable burden of monosodium urate crystals in the body, really the oral urate-lowering medications like Allopurinol and Febuxostat are often no longer effective. Those medications can prevent the production of uric acid, but they cannot really do anything about the uric acid that has already accumulated. That is where pegloticase, which is really the only option for these patients who failed other urate-lowering therapies, really can be dramatically effective at reducing the monosodium urate burden for these patients.

The mechanism of pegloticase is just simply fantastic. It can metabolize uric acid, turn it into soluble products. which are then in turn much more easily excreted by the kidneys. Nevertheless, it is an IV biologic; and as a biologic, it does have the capacity to cause immunogenicity or cause the production of anti-drug antibodies that both limit the effectiveness of the drug and make patients who take it at risk for infusion reactions during the administration of the medication.

Thus, the big unmet need for these patients is not just the fact that they have uncontrolled gout that is not responding to oral urate-lowering medications, but that they can get this dramatically effective medication but many of them, the medication is not effective because they may develop anti-drug antibodies.

With regard to safety, there can be infusion reactions to pegloticase. Twelve years now after pegloticase was approved by the Food and Drug Administration, there is still research being done to try and make this medication more effective for those patients who really need it. And that is exactly what the PROTECT randomized control trial sought to do. They have sought to use pegloticase in combination with other immunomodulatory medications to prevent the production of anti-drug antibodies.”
Medicom: How did the PROTECT study attempt to solve those problems?

“It is interesting, actually. PROTECT is a trial using pegloticase for patients with uncontrolled gout who also have kidney transplants. And the reason why that population was studied is for 2 reasons. One, patients with kidney transplants have a high prevalence of gout. They have reduced kidney function and they are taking medications. Often, that increases serum uric acid levels and makes them predisposed to getting gout. So, for example, some of the medications that they take to prevent rejection of their kidney transplant, notably the calcineurin inhibitors and some of the diuretics that are very commonly given to patients with a kidney transplant, also increased their uric acid levels. These patients have a high risk of getting gout. There are isolated reports of pegloticase efficacy in transplant recipients [3], but this question is largely unanswered.

At the same time, these medicines are on medications to prevent rejection of their kidney transplants. And so, the theory was that these medications would also reduce the immunogenicity or reduce their tendency to develop anti-drug antibodies. If you look at the PIVOTAL trial for pegloticase back in 2010, it showed that 42% of patients had a complete response, 58% of patients developed these anti-drug antibodies to the point that the drug was not effective for the 6-month endpoint. We all agree that only 42% level is just not good enough for these patients that really have no other options. For the PROTECT trial, all of these patients were on immunosuppression medications to protect their kidney transplant from rejection. And instead of a 42% response rate, the PROTECT trial found that those patients had an 89% response rate. Not only that, but in the PIVOTAL trial, 25% of patients had infusion reactions and in the PROTECT trial, none of the patients who were on immunosuppression had infusion reactions. We found that the drug was more than twice as effective, and there was also just a fraction of the risk involved. In fact, there were no infusion reactions at all.

Now in the new data that was presented at the American Society of Nephrology meeting, the so-called Kidney week in Orlando, was the actual anti-drug antibody and pharmacokinetic data for the patients that were enrolled in that trial. We had already reported the clinical response rate and we had already reported the safety profile for these patients with transplants taking pegloticase. But we really wanted to show a confirmation that for patients with kidney transplants, that they had higher drug exposures than patients who were not on any kind of immunomodulating therapy and they also had no production of anti-drug antibodies except for the two patients that had lost response. The 89% efficacy rate in this context is very promising. There were 2 patients who did develop anti-drug antibodies, and that is what the new data confirmed, was that it was in fact those 2 patients who lost response because of anti-drug antibody production.”


  1. Abdellatif, A. Pegloticase for Uncontrolled Gout in Kidney Transplant Recipients: Provisional Data Report of a Multicenter, Open-Label, Efficacy and Safety Study. ASN Kidney Week, presented Nov 4, 2022. ABSTRACT: PO2117.
  2. O’Dell JR et al. NEJM Evid 2022;1.
  3. Kilzer A, et al. Coadministration of Immunosuppressant Treatments With Pegloticase in the Context of Solid-Organ Transplantation and Gout: A Case Report. Exp Clin Transplant. 2022 May 23.

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